etude (study) phase i enox - unfractionated heparin (ufh)

Conditions: Thrombosis

Summary: primary objective: * to characterize the pharmacokinetic and the pharmacodynamic profile after intravenous bolus injection of unfractionated heparin (ufh) after repeated sc 100 iu anti-xa/kg (corresponding to 1 mg/kg) twice a day during 2.5 days (every 12±2hrs) administrations of enoxaparin in caucasian healthy subjects. secondary objective(s): * to compare the pharmacokinetic and the pharmacodynamic profile between 3 different timing of administration of the ufh * to assess the tolerability of the different anticoagulation protocols


Eligibility criteria:
inclusion criteria: * caucasian * male and female subjects, between 40 and 60 years of age * body weight between 50 kg and 90 kg if male and between 40 and 80 kg if female with body mass index (bmi) between 18 and 29 kg/m2 health status: * certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination) * subject with hypertension, hypo- or hyperthyroidism or dyslipidemia will be included if their concomitant pathology is well-controlled by treatment for at least one year * normal vital signs after 10 minutes resting in supine position: * 95 mmhg \< systolic blood pressure (sbp) \< 140 mmhg; * 45 mmhg \< diastolic blood pressure (dbp) \< 90 mmhg; * 40 bpm \< heart rate \< 100 bpm. * normal 12-lead electrocardiogram (ecg); 120 ms \< pr \< 220 ms, qrs \< 120 ms, qtc ≤ 430 ms for male, 450 ms for female or not considered as clinically significant by the investigator * laboratory parameters within the normal range unless the investigator considers an abnormality to be clinically irrelevant for healthy subjects; hepatic enzymes (aspartate amino-transferase or ast, alanine amino-transferase or alt) should be strictly below the upper laboratory norm. * platelets ≥ 150 000 / mm3 * mean corpuscular volume (mcv) and gamma glutamyl-transferase (ggt) should be strictly in the normal range of the laboratory * activated partial thromboplastin time (aptt) ratio should be comprised between 0.95 and 1.15 * estimated creatinine clearance by cockroft formula should be higher than 50 ml/min * non smoker or smoking the equivalent or less than 5 cigarettes a day and able not to smoke during the study hospitalization * normal gynecological examination no longer than 12 months before inclusion. * for female with childbearing potential using an effective contraception method (e.g. intra-uterine device, hormonal contraception, diaphragm and condom) except if postmenopausal for more than 12 months or sterilized for more than three months * subject with coagulation test and blood count (including platelets) within the physiological ranges) regulations: * having given written informed consent prior to any procedure related to the study * covered by health insurance system and/or in compliance with the recommendations of national law in force relating to biomedical research * not under any administrative or legal supervision exclusion criteria: medical history and clinical status: * contra-indication to anticoagulant therapy * subject with known increased bleeding time, hemophilia, thrombocytopenia, and/or history of any vascular purpura * subject with detectable antibody against heparin in the blood * any history or presence of clinically relevant cardiovascular, gynecologic (for women), pulmonary, gastro-intestinal, hepatic, renal, metabolic, hematological, neurologic, psychiatric, systemic, ocular or infectious disease that is capable of altering the absorption, metabolism, or elimination of drugs, or of constituting a risk factor when taking the study medication; any acute infectious disease or signs of acute illness; except subject with hypertension, hypo- or hyperthyroidism or dyslipidemia if well-controlled by treatment for at least one year. * subject with diabetes or other cardiovascular or metabolic disease * subject with inr \> 1.5 * frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month) * blood donation or blood loss within one month before administration * symptomatic hypotension whatever the decrease in blood pressure or asymptomatic postural hypotension defined by a decrease in sbp equal to or greater than 20 mmhg within three minutes when changing from the supine to the standing position * presence or history of drug allergy, or allergic disease diagnosed and treated by a physician * history or presence of drug or alcohol abuse (alcohol consumption \> 40 grams/day) * smoking more than 5 cigarettes or equivalent/day, or unable to stop smoking during the study * excessive consumption of beverages with xanthine bases (\> 4 cups or glasses/day) * pregnancy (defined as positive beta-hcg plasma test that can not be explicated by menopauses), breast-feeding for female, any history or presence of clinically relevant gynecologic disease interfering substance: * any medication (including st john's wort) within 14 days before administration, or within 5 times the elimination half-life of that drug, except for hormonal contraception or replacement therapy, and allowed therapy for stable pathology * anti-inflammatory treatments and anti-aggregant treatments are strictly forbidden during the whole study period general conditions: * subject who, in the judgment of the investigator, is likely to be non-compliant during the study, or unable to cooperate because of a language problem or poor mental development * subject in exclusion period of a previous study according to applicable regulations * subject who cannot be contacted in case of emergency * subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff thereof, directly involved in the conduct of the protocol or any other protocol of the investigating center * subject is an employee of the investigating center biological status: * positive reaction to any of the following tests: hbs antigen, anti-hcv antibodies, anti-hiv1 antibodies, anti-hiv2 antibodies, anti-lmwh antibodies * positive results on urine drug screen (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabinoids) * positive alcohol breath or plasma test